Since the 1950's, the delivery of locally acting medicaments to the respiratory tract, in the treatment of the reversible component of an obstructive airways disease, has largely involved administration using the metered dose inhaler (MDI). Over the last twenty years, the range of drugs administered by inhalation has increased to include: bronchodilators, corticosteroids, anticholinergics, the prophylactic agents sodium cromoglycate and nedocromil sodium.
Further, the art teaches the use of aerosol propellants as a method of obtaining local anesthesia in the bronchial airways using lignocaine aerosol and the administration of nebulized morphine to relieve dyspnea.
Metered dose inhalers (MDI's), formulated as suspensions of a micronised drug in a chlorofluorocarbon (CFC) formulation, represent a major device for the delivery of locally active drugs used in the treatment of respiratory disorders and are well known in the art. Despite the identification and optimization of the major parameters which influence the performance of MDI's such as particle size, vapor pressure, and surfactant concentration (Poli et al., M. H. J. Pharm. Sci., 58 (1969) 484), their use in practice results in extensive extrapulmonary deposition with frequently less than 10 percent of the metered dose actually reaching the targeted site.
In the past, metered dose inhalers (MDI's) formulations have been heterogeneous systems which require redispersion prior to use of the medicinal aerosol. These formulations suffer from the drawback that they are prone to agglomeration of the finely divided drug particles, which can lead to the formation of `cakes`. Further, low levels of solubility may be manifested as crystal growth which can lead to changes in the size distribution of the suspended solid. Either of these phenomena can result in inadequate delivery of the desired amount of the drug.
The present invention seeks to overcome these problems of prior art aerosol systems through the formulation of a homogeneous colloidal dispersion system in contrast to both heterogeneous (suspension) systems and homogenous systems which include co-solvents such as ethanol.
Pharmaceutical pressurized pack dosage forms contain the therapeutically active ingredient dissolved or suspended in a propellant system which is capable of expelling the contents of the pack through an opened valve. For potent drugs, such as those used in the treatment of bronchial asthma, the valve includes a metering device that delivers a measured volume typically in the range of 25-100 .mu.L. The prior art inhalation packs also contain a small percentage of surfactant which acts as a suspending agent, and, to a lesser extent, as a lubricant for the metering valve assembly.
Prior art solutions also generally included a high boiling point co-solvent, such as ethanol, which is miscible with the chlorofluorocarbon formulation. These were even more inefficient than present day devices because they decreased the rate of evaporation of propellant from the aerosol droplets.
Inhalation devices offer the advantage of delivering drugs directly to the required site of action and in doing so, avoid `systemic` first-pass metabolism. Pulmonary first-pass metabolism may occur, but the activity of enzymes found in the lungs is generally lower than corresponding enzymes in the liver. The amount of drug required to bring about a pharmacological response can be much smaller than that required when the drug is administered by another route, and thus, the incidence and severity of any potential side-effects can also be reduced. Furthermore, for compounds with rapid absorption, local action can be immediate, and the potential of systemic delivery also exists.
As a result of a combination of factors in the administration process, the release of a large and rapidly moving aerosol bolus and the physical constraints of the tracheabronchial tree, the majority of the metered dose for an MDI fails to reach the intended site of action, mainly through deposition in the orapharyngeal region. This means that while the pharmacological response is efficacious, the administration of the drug is brought about in an inefficient manner. Typically, a loss of drug of between 80 to 90 percent is often encountered which, provided the required pharmacological response occurs, is of little concern in the case of compounds with few localized side-effects and for those which are inactivated in the GI tract. However, with corticosteroids, deposition in the oropharynx can result in fungal overgrowth due to the immunosuppressive side effects of these compounds.
For pressurized packs used under optimal conditions, only some 10-14 percent of the metered dose is deposited in the bronchial tree. Deposition can be improved by using a spacer in conjunction with the MDI and increases to around 15 percent with the Nebuhaler.RTM. and Inspir Ease.RTM. devices. In separate research using an open spacer, Newman and co-workers demonstrated an increase in dose reaching the lung from 11 percent to between 13 and 16 percent (depending on breathing pattern) for an Intal.RTM. inhaler.
U.S. Pat. No. 4,814,161 to Jinks et al. discloses the existence of reverse micellization and the self association of non-ionic surfactants in apolar media. Jinks et al. discloses a technique for incorporating drugs into chlorofluorocarbon aerosol propellants with the addition of a co-solvent, such as ethanol. Jinks et al. does not disclose the exclusion of moisture associated with the surfactant prior to formulation in order to prevent phase separation, which is produced by excess water. Jinks et al. further does not teach the manipulation of the water pool through the addition of water to make it more or less suitable as a site for solubilization.
Amphiphatic molecules in apolar media may associate into reversed or inverted micellar solutions (Luisi et al, Biochim. Biophysi. Acta, 947 (1988) 209) which are homogeneous and optically transparent and have the ability to solubilize quantities of water. The result of incorporating water into such systems is the production of a water-pool and the formation of swollen micelles, which serve as centers for the solubilization of drugs of various physico-chemical characteristics.
The use of therapeutic concentrations of a model bronchodilator solubilized in heterogeneous systems is disclosed in an article, Evans et al, "Surfactant Association and Water Uptake in a Model Chlorofluorocarbon System," J. Pharm. Pharmacol., 39 (1988) 7P. This article discusses the potential for solubilizing drugs through the alteration of the size and polarity of reverse micelle structure.